Cross-Species analysis defines the conservation of anatomically-segregated VMH neuron populations

  1. Alison H Affinati
  2. Paul V Sabatini
  3. Cadence True
  4. Abigail J Tomlinson
  5. Melissa Kirigiti
  6. Sarah R Lindsley
  7. Chien Li
  8. David P Olsen
  9. Paul Kievit
  10. Alan C Rupp
  11. Martin G Myers Jr  Is a corresponding author
  1. University of Michigan, United States
  2. Oregon National Primate Research Center, United States
  3. Novo Nordisk Research Center, United States

Abstract

The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing Translating Ribosome Affinity Purification with RNA sequencing (TRAP-seq) data with snRNA-seq data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of 6 major genetically- and anatomically-differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously-suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.

Data availability

Sequencing data have been deposited in GEO under accession code GSE172207

The following data sets were generated

Article and author information

Author details

  1. Alison H Affinati

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  2. Paul V Sabatini

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6613-566X
  3. Cadence True

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    No competing interests declared.
  4. Abigail J Tomlinson

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  5. Melissa Kirigiti

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    No competing interests declared.
  6. Sarah R Lindsley

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    No competing interests declared.
  7. Chien Li

    Obesity, Novo Nordisk Research Center, Seattle, United States
    Competing interests
    Chien Li, is an employee of Novo Nordisk A/S.
  8. David P Olsen

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  9. Paul Kievit

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    No competing interests declared.
  10. Alan C Rupp

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5363-4494
  11. Martin G Myers Jr

    Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    For correspondence
    mgmyers@umich.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9468-2046

Funding

National Institutes of Health (dk056731)

  • Martin G Myers Jr

Novo Nordisk

  • Martin G Myers Jr

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ana Domingos, University of Oxford, United Kingdom

Ethics

Animal experimentation: All mice used in this study were maintained in accordance with University of Michigan Institutional Animal Care and Use Committee (IACUC), Association for the Assessment and Approval of Laboratory Animal Care (AAALAC) and National Institutes of Health (NIH) guidelines under protocol number PRO00007438 (PI Myers).Nonhuman primate tissue was obtained post-mortem from the Tissue Distribution Program at ONPRC. Animal care is in accordance with the recommendations described in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and animal facilities at the Oregon National Primate Research Center (ONPRC) are accredited by the American Association for Accreditation of Laboratory Animal Care International. ONPRC does not provide protocol numbers for security reasons.

Version history

  1. Received: April 2, 2021
  2. Accepted: May 14, 2021
  3. Accepted Manuscript published: May 21, 2021 (version 1)
  4. Accepted Manuscript updated: May 24, 2021 (version 2)
  5. Version of Record published: June 7, 2021 (version 3)

Copyright

© 2021, Affinati et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,364
    views
  • 262
    downloads
  • 20
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Alison H Affinati
  2. Paul V Sabatini
  3. Cadence True
  4. Abigail J Tomlinson
  5. Melissa Kirigiti
  6. Sarah R Lindsley
  7. Chien Li
  8. David P Olsen
  9. Paul Kievit
  10. Alan C Rupp
  11. Martin G Myers Jr
(2021)
Cross-Species analysis defines the conservation of anatomically-segregated VMH neuron populations
eLife 10:e69065.
https://doi.org/10.7554/eLife.69065

Share this article

https://doi.org/10.7554/eLife.69065

Further reading

    1. Cell Biology
    2. Neuroscience
    Jaebin Kim, Edwin Bustamante ... Scott H Soderling
    Research Article

    One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associated with hippocampal-dependent working memory and longer-term forms of learning and memory and that Rac1 can modulate forms of both pre- and postsynaptic plasticity. How these different cognitive functions and forms of plasticity mediated by Rac1 are linked, however, is unclear. Here, we show that spatial working memory in mice is selectively impaired following the expression of a genetically encoded Rac1 inhibitor at presynaptic terminals, while longer-term cognitive processes are affected by Rac1 inhibition at postsynaptic sites. To investigate the regulatory mechanisms of this presynaptic process, we leveraged new advances in mass spectrometry to identify the proteomic and post-translational landscape of presynaptic Rac1 signaling. We identified serine/threonine kinases and phosphorylated cytoskeletal signaling and synaptic vesicle proteins enriched with active Rac1. The phosphorylated sites in these proteins are at positions likely to have regulatory effects on synaptic vesicles. Consistent with this, we also report changes in the distribution and morphology of synaptic vesicles and in postsynaptic ultrastructure following presynaptic Rac1 inhibition. Overall, this study reveals a previously unrecognized presynaptic role of Rac1 signaling in cognitive processes and provides insights into its potential regulatory mechanisms.

    1. Neuroscience
    Qiaoli Huang, Huan Luo
    Research Article

    Daily experiences often involve the processing of multiple sequences, yet storing them challenges the limited capacity of working memory (WM). To achieve efficient memory storage, relational structures shared by sequences would be leveraged to reorganize and compress information. Here, participants memorized a sequence of items with different colors and spatial locations and later reproduced the full color and location sequences one after another. Crucially, we manipulated the consistency between location and color sequence trajectories. First, sequences with consistent trajectories demonstrate improved memory performance and a trajectory correlation between reproduced color and location sequences. Second, sequences with consistent trajectories show neural reactivation of common trajectories, and display spontaneous replay of color sequences when recalling locations. Finally, neural reactivation correlates with WM behavior. Our findings suggest that a shared common structure is leveraged for the storage of multiple sequences through compressed encoding and neural replay, together facilitating efficient information organization in WM.